Intended for healthcare professionals


Survey of unlicensed and off label drug use in paediatric wards in European countries

BMJ 2000; 320 doi: (Published 08 January 2000) Cite this as: BMJ 2000;320:79

The paediatric rule

The paediatric rheumatic diseases (PRD) are rare conditions,
associated with substantial morbidity, and monetary costs. Drugs for the
treatment of PRD are now being used in new dosages, new routes of
administration, new combinations and for complications of disease but data
regarding the safety and efficacy of these new treatment regimens tends to
be from small, anecdotal, uncontrolled, non-randomised case series.
Moreover all the drugs currently used for the treatment of the PRD in most
if not all the European countries, are used off label since no indication
for paediatric use is reported in the drug label.

Certainly chronic illnesses of childhood with the potential for
producing high levels of morbidity should be the target of intense
research aimed at amelioration and possibly curing the disease. Yet, for
many reasons, securing funding for conducting clinical trials in PRD has
always been difficult. The pharmaceutical industry for example, has little
interest in funding trials in PRD and for children in general: the
potential market in children is small, most of the childhood chronic
conditions are considered orphan illnesses, and moreover due to the rarity
of most of the paediatric conditions, enrolment periods must necessarily
be long while pharmaceutical companies demand a relatively short enrolment

To face these problems in May 1996 a European research network called
"Paediatric Rheumatology International Trials Organisation - PRINTO" was
founded initially by 14 European countries (now 32 countries world wide)
with the goal to facilitate and co-ordinate the development, conduct,
analysis, and reporting of clinical trials in children with PRD. PRINTO
was founded with the idea to perform clinical trials for the PRD with or
without the support of pharmaceutical companies.

In 1997 PRINTO obtained a 3 years grant support from the European
Union (EU) to conduct, a clinical trial entitled: "A randomised actively
controlled clinical trial in children with juvenile chronic arthritis
(JCA): parenteral methotrexate in medium versus higher doses in children
who failed on standard dose of methotrexate". Important funding are coming
entirely from the EU with no pharmaceutical company supporting the trial.
This trial is built on the current "standard of care" in such a way that
the cost of insurance coverage, the medication, clinic visits, and
laboratory monitoring, are paid by the usual method of cost reimbursement
for clinical care in each participating country. The amount of data to be
collected, in addition to that from routine follow-up, is minimal, and all
participants volunteer the effort. As of today we have been able to enrol
more than 250 patients from 18 countries world wide. Interesting ethics
committee approval has been denied in 4 other countries because of lack of
insurance coverage (to be covered internally by the participating
hospitals), because medication were not administered free of charge (to be
paid with the usual methods of cost reimbursement), because of lack of the
support from a pharmaceutical company.

The problems faced by PRINTO, and surely other paediatric
organisation in dealing with pharmaceutical companies and ethics
committees, clearly underline the difficulties to design and conduct
clinical trials for children with rare diseases and for children in
general, especially if the issue is a trial seeking for approval from
regulatory agencies.

As stated by Conroy S et al 1 the "European Medicines Evaluation
Agency - EMEA"2 has issued the European guidance on the clinical
investigation of medicinal products in children 3, but this guidance
simply encourages pharmaceutical companies that wish to introduce new
products to investigate these in children when clinical appropriate. The
same difficulties lead the Food and Drug Administration (FDA) to issue the
so-called "paediatric rule"4. The "Rule," effective April 1, 1999,
specifies "Regulations Requiring Manufacturers to Assess the Safety and
Effectiveness of New Drugs and Biological Products in Pediatric Patients."
This regulation directs the manufacturers of certain products likely to be
used in children to study those products in the relevant paediatric
population, so that data and information sufficient to support directions
for paediatric use could be made available (modification of the Food and
Drug Administration Modernization Act of 1997 5; 6).

As Conroy et al we urge the European Union and the EMEA to issue a
similar paediatric rule for the European Community to assure children and
their families the same rights than adults to receive drugs fully tested.

1 Nicolino Ruperto, MD, MPH

2 Alberto Martini, MD,
Prof for the
"Paediatric Rheumatology International Trials Organisation -PRINTO"

1 Laboratorio di Informatica Medica, and 2 Clinica Pediatrica, IRCCS S.
Matteo, University of Pavia, Italy,
e-mail: or

Reference List

1. Conroy S, Choonara I, Impicciatore P, et al. Survey of unlicensed
and off label drug use in paediatric wards in European countries. BMJ

2. European Medicines Evaluation Agency - EMEA. Report on the experts
round table on the difficulties related to the use of new medicinal
products in children held on 18 December 1997. EMEA 1998;27164/98 Rev. 1:

3. European Medicines Evaluation Agency - EMEA. Note for guidance on
clinical investigation of medicinal products in children. London: EMEA

4. Connor JD. A look at the future of pediatric therapeutics: an
investigator's perspective of the new pediatric rule. Pediatrics

5. Food and Drug Administration (FDA). Food and Drug Administration
Modernization Act of 1997. Food and Drug Administration Modernization Act
of 1997 1997;USA Public Law 105-115 Nov. 21, 1997:

6. Food and Drug Administration (FDA). Regulations requiring
manufacturers to assess the safety and effectiveness of new drugs and
biologic products in pediatrics patients (21 CFR Parts 201, 312, 314, and
601). Federal Register 1998;63:

Competing interests: No competing interests

28 January 2000
Nicolino Ruperto
Medical Doctor Laboratorio Informatica medica, Professor of Pediatrics at Clinica Pediatrica
Alberto Martini
IRCCS S. Matteo, University of Pavia, Italy